LIETUVOS CHIRURGIJA Lithuanian Surgery
2013, 12 (3), p. 138–143
Treatment methods of prostate cancer
recurrence after radiotherapy
Current treatment alternatives and our clinical experience
Prostatos vėžio recidyvų po spindulinės terapijos gydymo metodai
Šiuolaikinėje medicinoje naudojami metodai ir mūsų klinikinė patirtis
Albertas Ulys
1, Alvydas Vėželis
1, Andrius Ivanauskas
1, Marius Snicorius
21 Institute of Oncology of Vilnius University, Santariškių 1, LT-08660 Vilnius 2 Vilnius University, Faculty of Medicine
E- mail: Marius.Snicorius@gmail.com
Background / objective
Prostate cancer is the most common cancer among men of Lithuania. Every year about 3000 new cases of prostate cancer are diagnosed in our country. Many patients receive radiotherapy as primary treatment. Unfortunately, after several years some of the patients are diagnosed with prostate cancer recurrence. These cases are more challenging and require to apply salvage treatment methods. The aim of this article is to present our clinical experience and discuss the main features, advantages and disadvantages of the treatment methods.
Patients and methods
Retrospective analysis of 10 salvage prostate cancer recurrence treatment cases was completed. All patients previously re-ceived radiotherapy as primary treatment. 5 patients rere-ceived salvage high- dose brachiterapy (group 1) and other 5- salvage cryotherapy (group 2). Prostate cancer recurrences were diagnosed by multiparametric MRI and ultrasound guided transrec-tal or transperineal biopsies.
Results
Average patient age was 64,2±7,9 years in group 1 and 68±3,1 years in group 2. None of the patients had prostate cancer progression to lymph nodes (N) or metastases (M) on initial diagnosis or before salvage treatment. No intraoperative compli-cations were observed. Average time between radiotherapy and salvage therapy in both groups was 88,9±30,1 months. In both groups 1 patient suffered from salvage treatment failure- prostate cancer progression was observed.
Conclusions
Currently there is no perfect treatment method for recurrent prostate cancer. Every situation requires universal aproach. Our initial experience shows that salvage cryotherapy and brachiterapy can be a viable alternative for patients with disease pro-gression after radiotherapy.
Introduction
Prostate cancer is the most common cancer among men of Lithuania. Every year about 3000 new cases of prostate cancer are diagnosed in our country. Many patients receive radiotherapy as primary treatment. Un-fortunately, after several years some of the patients are diagnosed with prostate cancer recurrence. These cases are more challenging and require to apply salvage tre-atment methods. Radical prostatectomy, cryotherapy, high- dose radiotherapy, hormone therapy, high- inten-sity focused ultrasound or active surveillance- any of it can be used for prostate cancer reccurence treatment. The aim of this article is to present our clinical expe-rience and discuss the main features, advantages and disadvantages of treatment methods.
Patients and methods
Recently, in Vilnius university Oncology institute 10 salvage treatment procedures for prostate cancer re-currences were performed. Retrospective analysis of these cases was completed. 5 patients (50%) received salvage high- dose brachiterapy (Group 1) and other 5 received 2-cycle salvage cryotherapy (Group 2) with
Įvadas / tikslas
Lietuvoje kasmet nustatoma apie 3000 naujų prostatos vėžio atvejų. Daugeliui pacientų taikomas spindulinis gydymas. Deja, praėjus keletui metų, kai kuriems pacientams diagnozuojamas prostatos vėžio recidyvavimas. Šiuo metu yra daug gydymo metodų, bet dažnai iškyla problemų pasirenkant optimalų. Šio straipsnio tikslas – pasidalinti mūsų klinikine patirtimi bei ap-žvelgti prostatos vėžio recidyvų po spindulinės terapijos gydymo alternatyvas.
Pacientai ir metodai
Retrospektyviai buvo išanalizuota dešimt pacientų, kuriems po pirminio gydymo radioterapija buvo diagnozuotas prostatos vėžio recidyvavimas. 5 pacientai buvo gydomi didelių dozių brachiterapija (1 grupė), o likusiems 5 buvo skirta krioterapija (2 grupė). Prostatos vėžio recidyvai diagnozuoti multiparametriniu kontroliuojant MRT ir ultragarsu atliktomis transrektalinė-mis ir transperinealinėtransrektalinė-mis prostatos biopsijotransrektalinė-mis.
Rezultatai
Pirmoje grupėje vidutinis pacientų amžius buvo 64,2±7,9 metų, o antroje grupėje 68±3,1. Nė vienam pacientui nebuvo nu-statytas prostatos vėžio išplitimas į limfmazgius (N) ar metastazavimas (M). Intraoperacinių komplikacijų nepasitaikė. Viduti-niškai tarp pirminės radioterapijos ir gelbstinčio prostatos vėžio recidyvavimo gydymo praėjo 88,9±30,1 mėnesio. Gelbstintis prostatos vėžio recidyvavimo gydymas buvo nesėkmingas dviem atvejais – po vieną atvejį abiejose grupėse.
Išvados
Šiuo metu nėra tobulo gydymo tų pacientų, kuriems prostatos vėžys recidyvavo po spindulinio gydymo. Tokiais atvejais rei-kalingi unikalūs sprendimai. Mūsų nedidelė pirmoji patirtis rodo, jog gelbstinčioji krioterapija ir brachiterapija – tinkami me-todai gydyti pacientams, kuriems recidyvavo prostatos vėžys po spindulinės terapijos.
Reikšminiai žodžiai: prostatos vėžys, prostatos vėžio recidyvai, gelbstintis gydymas.
real-time ultrasound guidance, urethra-warming cathe-ter and temperature change tracking. All patients pre-viously received radiotherapy as primary treatment for prostate cancer. Radiation dose was 68-72 Gy. Prostate cancer recurrences were diagnosed by multiparametric MRI and ultrasound guided transrectal or transperineal biopsies. MRI findings were validated with Magnetic Resonance Prostate Imaging Reporting and Data Sys-tem (PI-RADS). CT, MRI, ultrasound scanning, bone scintigraphy was performed for patients before treat-ment. No pathological bone changes were detected.
The analyzed factors in both groups were: age, pro-state cancer stage on initial diagnosis (TNM), PSA on initial prostate cancer diagnosis, PSA before salvage therapy, time between primary radiotherapy and salva-ge treatment, Gleason score on initial diagnosis, salvasalva-ge brachiterapy radiation dose, intraoperative and posto-perative complications.
Data analysis was performed using SPSS software version 17 (SPSS, Chicago, IL, USA).
Results
Average patient age was 64,2±7,9 years in group 1 and 68±3,1 years in group 2. None of the patients
stay with epicystostomy and over-went prostate transu-rethral resection. After these procedures patient could urinate normally. One patient had biochemical pro-gression due to metastasis in parailiacal lymph node, and he got external beam therapy to lymph-node pro-jection. After 6 months there were no signs of cancer progression on MRI and PSA was 1,77 ng/ml.
Discussion
Biochemical failure in men who have undergone exter-nal beam radiation therapy (EBRT) for localized pro-state cancer can occur in approximately 10% to 30% [1-3]. The biochemical control rates are significantly better with high-dose radiation compared with conven-tional doses. PSA relapse-free survival rates after prima-ry definitive radiation therapy are between 62% and 81%, depending on risk grouping [4].
Differentiating between local recurrence and metas-tatic disease is very important. Traditionally, bone scans and CT scans have been the tests of choice, along with physical examination, to define disease progression. Evaluation of PSA kinetics (doubling time and velo-city) may be a useful tool that further aids in differen-tiating between local recurrence and metastatic disease. Quickly rising PSA may indicate distant disease while a more moderate rate of PSA rise may indicate local disease recurrence [5]. In patients with local recurrence, PSA doubling time is greater than 6 months and in tho-se with systemic recurrence PSA doubling time is less than 3 months [5]. More over, if PSA doubling time is < 10 months, the 7-year survival after radiation therapy is only 52% [6,7].
Other authors suggests that there is no definitive predictors of local recurrence after radiotherapy. Several features have been associated with a higher likelihood of systemic rather than local disease, including a rapidly rising post-treatment PSA level, short PSA doubling time, poorly differentiated cancer (Gleason score 8–5), and a short disease-free interval after radiotherapy, no individual factor is definitively associated with metas-tatic progression nor eliminates the possible benefit of local salvage therapy [8;9].
Most men who fail EBRT receive androgen-depri-vation therapy (ADT), which can have an impact on quality of life and cardiac, metabolic, and bone health had prostate cancer progression to lymph nodes (N)
or metastases (M) on initial diagnosis or before salva-ge treatment. Cancer tumor stasalva-ges on initial prostate cancer diagnosis (T) in group 1: 2 patients (40%) had cT1c, 2 patients (40%) cT2b, 1 (20%) patient cT3a; in group 2: 3 (60%) patients had cT2b, 1 (20%) patient cT3a and 1 (20%) patient cT1c. Gleason score on ini-tial diagnosis in group 1 was 6 in 4 cases (80%) and 8 in 1 case (20%); in group 2 Gleason score was 6 in all cases (100%).
Time between radiotherapy and salvage treatment in group 1 was 90±36 months; in group 2- 87,2±26,4 months. Average time between radiotherapy and salva-ge therapy in both groups was 88,9±30,1 months.
In group 1 PSA on cancer diagnosis was 14,3±6,7 ng/ml, on cancer recurrence diagnosis 7,4±4,9 ng/ml. In group 2 PSA on cancer diagnosis was 21,5±13,4 ng/ ml, on cancer recurrence diagnosis 2,7±2,3 ng/ml. In group 1 only one patient was followed up more than 6 months. Other patients received their salvage brachite-rapy very recently and PSA was not checked yet. Ho-pefully in the near future, we will be able to share lon-ger follow-up time results of these patients. In group 2 PSA after salvage cryotherapy was 0,4±0,7 after 5±1,7 months of follow- up.
In group 1 every patient had two procedures of bra-chiterapy with few days break between them. 4 patients (80%) received 11 Gy and 1 patient (20%) 9 Gy dose for prostate during each procedure.
No intraoperative complications were observed. No patients suffered from urinary incontinence. However, one patient (20%) who had highest PSA before treat-ment (15,21 ng/ml) developed dysuria like symptoms after brachiterapy. Unfortunately, 2 months after sal-vage brachiterapy PSA of the same patient rose up to 93,16 ng/ml and he was diagnosed with metastases in his vertebrae. Currently, he is suffering from pain syn-drome and is treated with chemotherapy.
In group 2 patients received 2-cycle cryotherapy with real-time ultrasound guidance, urethra-warming catheter and temperature change tracking.
All procedures were completed succesfully without any intraoperative complications. No patients suffered from urinary incontinence. Urinal obstruction was observed after 1 week for 1 of 5 patients. He had to
[10,11]. Consistent evidence shows that ADT cannot be considered a curative treatment for patients with locally recurrent prostate cancer [12]. However, many patients have localized disease that may be suitable for local salvage therapy using surgery, brachytherapy, cry-otherapy, or high-intensity focused ultrasound (HIFU). Historically open salvage prostatectomy (SRP) is associated with high risk of complications and bad outcomes. However, recent studies reported much bet-ter results and lower complication risk. Brazilian study published some interesting facts about open salvage prostatectomy. Blood loss during operation superior to 600 mL occurred in only 14% of the patients. None of them required blood transfusion. However other complications were higher than expected: stenosis/scle-rosis of the vesicourethral anastomosis 50%, urinary in-continence, de fined as two or mores pads required daily was 72%, nearly 74% of the patients reported worse erectile function. Intraoperative rectal injury rate was 2% although, other authors reported rate fom 0% to 19% [13].
Other study, which is one of the biggest ones, ana-lyzed open SRP results of 404 patients. At 5 years after SRP, the probabilities of being free from biochemical cancer recurrence, metastasis, and cancer-specific death were 48%, 83% and 92% respectively; at 10 years, the probabilities were 37%, 77% and 83%, respectively. They also concluded that higher PSA before operation, and higher Gleason score after operation are associated with higher risk of BCR and metastasis. Lymph node involment before operation is also predictor of metas-tasis [14]. Salvage robotic-assisted laparoscopic prosta-tectomy has lower complication rates than open SRP, but, unfortunately, this procedure is not currently per-formed in Lithuania.
Salvage radiotherapy is rarely used for prostate can-cer radiation failures. Only few studies analyzed such treatment method results. Grado et al. treated 49 pa-tients with transperineal TRUS-guided brachytherapy after radiotherapy and published that biochemical dise-ase- free rate at 3 years is 48%, at 5 years- 34%. The in-cidence of serious complications after salvage brachyt-herapy, such as incontinence and rectal complications, was lower than that reported after other types of salvage procedures [15]. In many cases salvage brachiterapy or
external beam re- radiotherapy is not an option for pro-state cancer recurrence treatment because of too high cummulative radiation dose (external beam therapy already brings at least 70 Gy radiation dose)
Additional radiotherapy also brings toxic compli-cations. Moman et al. study analyzed results of salvage iodine-125 implantation in 31 patients: Grade 1, 2, or 3 toxicity of the gastrointestinal tract was reported in 45%, 10%, and 0% of the patients, respectively, in the acute phase, and in 48%, 3%, and 6%, respectively, in the late phase. Both genitourinary and gastrointestinal toxicity occur frequently [16].
Other local salvage therapy- cryotherapy. It can be used for patients who are not good candidates for con-ventional surgery because of their age or other medical conditions.
Patients undergoing salvage cryoablation tend to have a significantly higher complication rate compa-red with men undergoing primary treatment due to the retreatment of irradiated, poorly vascularized, ana-tomically altered tissue. Although now over a decade old, in perhaps the largest study among salvage cry-otherapy patients, 72% of men reported some degree of dribbling or leakage at a mean follow-up of 16.7 months [16]. The technology of cryoablation devices has been improved, urethra warming catheter was ad-ded and the development of new-generation real-time
Fig. 1. Placement of freezing probes during cryotherapy
ultrasound probes as a guide for freezing ablation al-lows safer and more precise treatments than in the first experiences. More recent Finley et al. study analyzed up-to-date oncologic and functional outcomes, as well as complications of salvage cryotherapy for radiation-recurrent prostate cancer and reported 21.7% urinary incontinence rate [18]. Other new study reported even better results: long term incontinence rate was 12% (using 1 pad per day beyond 6 months post-salvage cryotherapy) and fistula rate of 1.8% [19].
Biochemical failure rates after salvage cryotherapy vary not only according to the definition of failure, but also due to the generation of the cryounit, cycling para-meters, clinicopathologic characteristics, and length of follow-up. Across most definitions, biochemical failure-free rates vary from 59% to 74% [20]. Recently, a lar-ge multi-institutional study comprising a pool of 450 salvage patients was published by Spiess and colleagues with the intent to create a pretreatment nomogram. At a median follow-up of 3.4 years, the overall rate of biochemical failure was 66% (PSA >0.5 ng/mL) [21]. Williams et al. reported an 87% 10-year overall survival rate in men undergoing salvage cryoablation; the dise-ase-specific survival and disease-free survival were 64% and 39%, respectively. In terms of prognostic factors, they found a PSA nadir above 1.0 ng/mL was signifi-cantly associated with poor prognosis [22].
One study evaluated financial implications of locali-zed prostate cancer treatment methods. Despite the re-latively increased surgical expense of cryotherapy com-pared with conventional surgical prostatectomy (open, laparoscopic or robotic), the overall direct costs were offset by the significantly lower nonoperative hospital costs. The cost advantages associated with cryotherapy included a shorter length of stay in the hospital and the absence of pathologic costs and the need for blood transfusion [23].
High- intensity focused ultrasound
The experience of high-intensity focused ultrasound (HIFU) for the treatment of locally recurrent prostate cancer after radiation therapy is limited to a few retros-pective studies and nature of this treatment modality still is experimental due to the short follow-up periods
reported. A pilot study reported results of focal salvage therapy using high-intensity focused ultrasound. The actual progression-free survival rate (including PSA nonresponders) was 69% at 1 year and 49% at 2 years according to Phoenix criteria [24]. Almost same authors previously published results of salvage whole prostate HIFU. 1- and 2-year progression-free survival rates were 59% and 43%. Complication rates were: 38% urinary incontinence, erectile function scores decreased significantly, rectourethral fistula rate after 1 treatment was 2.4%, but 33% after a redo-salvage procedure [25].
Conclusions
Currently there is no perfect treatment method for re-current prostate cancer. Every situation requires univer-sal aproach.
Salvage radical prostatectomy (SRP) is a good op-tion for patients who has less co- morbidities and can survive major surgery. At 5 years after SRP, the pro-babilities of being free from biochemical cancer recur-rence, metastasis, and cancer-specific death were 48%, 83% and 92% respectively; at 10 years, the probabili-ties were 37%, 77% and 83%. However, higher risk of complications must be considered.
Cryotherapy is another really effective treatment which can be used if patient can not be operated. It brings similar oncological outcomes: biochemical fai-lure-free rates vary from 34% to 74% for follow up periods up to 10 years. Other advantages are: cheaper overall cost than SRP, lower complication risk.
Experience of salvage radiotherapy and high-inten-sity-focused ultrasound is limited and should be reser-ved for experimental studies until more longer term data will be available.
Androgen deprivation therapy cannot be considered as a curative treatment for patients with locally recur-rent prostate cancer and should be used for metastatic disease progression or patients with local disease recur-rence who reject any other treatment alternatives.
Our initial experience shows that salvage cryothe-rapy and brachitecryothe-rapy can be a viable alternative for patients with disease progression after radiotherapy. However, larger study with longer follow-up time is necessary to verify oncological and functional results.
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